Autoimmune diseases are believed to involve immune responses to the body's own components that are not observed under normal conditions, which result in a pathological state that causes various tissue disorders and/or functional disorders. Autoimmune diseases are broadly classified into systemic autoimmune diseases and organ-specific autoimmune diseases according to their characteristics. Typical examples of systemic autoimmune diseases include systemic lupus erythematosus and chronic rheumatoid arthritis. On the other hand, typical examples of organ-specific autoimmune diseases include Hashimoto's disease and juvenile-onset type diabetes.
The mechanism of cell tissue disorder is mainly classified into a disorder mechanism mediated by antibodies and immune complexes (referred to as the "humoral immunity-mediated disorder mechanism") and a disorder mechanism mediated by T-lymphocytes and other cells (Cell-mediated cytotoxicity, referred to as the "cellular immunity-mediated disorder mechanism"). In general, the humoral immunity-mediated disorder mechanism is considered to be important in systemic autoimmune diseases, while the cellular immunity-mediated disorder mechanism is considered to be important in organ-specific autoimmune diseases.
However, due to recent progress in the field of immunology, it has been clearly shown that in the cellular immunity-mediated disorder mechanism, in addition to cytotoxic cells consisting primarily of lymphocytes gathering near the target cells followed by ultimately making direct contact with the target cells to impair them, cytotoxic cells also release humoral factors such as inflammatory cytokines (such as TNF, IL-1 and LT) which indirectly impair the target cells as a result of their mediation. On the other hand, in the humoral immunity-mediated disorder mechanism as well, it has also been clearly shown that there is, for example, an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism in the case of the involvement of cells such as killer lymphocytes, neutrophils and platelets [Byourigakutaikei, Suppl. 1, pp. 91-105 (1995)].
Thus, in the target internal organ or target organ disorder mechanism in autoimmune diseases, regardless of whether they are systemic autoimmune diseases or organ-specific autoimmune diseases, invasion by cytotoxic cells consisting primarily of lymphocytes is considered to be important in terms of causing various tissue and functional disorders. For this reason, compounds that inhibit invasion of lymphocytes in the above-mentioned target internal organ or target organ are useful as agents for prevention or treatment of autoimmune diseases.
Steroids, non-steroidal anti-inflammatory agents, immunosuppressants and so forth are currently used in the treatment of autoimmune diseases [Konnichinochiryoushishin, Igaku Shoin, p. 577 (1996)]. In addition, agents that inhibit the production and action of inflammatory cytokines such as TNF.alpha. and IL-1 have recently been developed. Further, various types of mouse monoclonal antibodies to cell adhesion factors (such as ICAM-1 and VCAM-1) have been developed for the purpose of inhibiting the invasion of cytotoxic lymphocytes into the target internal organs and target organs. The therapeutic effects of these monoclonal antibodies have been reported in various animal models such as DBA/2 mice [Yagi, et al., Diabetes, 44, 744 (1995); Baron, et al., J. Clin. Invest., 93, 1700 (1994)]. However, none of these therapeutic agents or therapeutic methods exhibits adequate effects, and they also have the disadvantage of serious adverse effects. There is therefore the desire for a preventive or therapeutic agent for autoimmune diseases having excellent clinical efficacy and weaker adversity.
In recent years, substances that improve insulin resistance are known to function as agents for preventing or treating diabetes. Here, insulin resistance improving substances refer to compounds that improve impaired insulin action despite the presence of endogenous insulin. These substances that improve insulin resistance include a wide range of compounds. Typical examples include thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds. These compounds are disclosed in WO 94/01433 (=Japanese Patent Application (Kokai) No. Hei 6-80667; Japanese Patent Application (Kokai) No. Hei 4-69383; WO 92/02520 (=Japanese Patent Application (Kohyo) No. Hei 6-500538); WO 91/07107 (=Japanese Patent Application (Kokai) No. Hei 3-170478=Japanese Patent Publication (Kokoku) No. Hei 7-8862); U.S. Pat. No. 5,132,317 (=Japanese Patent Application (Kokai) No. Hei 3-90071); U.S. Pat. No. 4,897,405 (=Japanese Patent Application (Kokai) No. Hei 2-292272); WO 89/08651 (=Japanese Patent Application (Kokai) No. Hei 1-272574); U.S. Pat. Nos. 5,061,717, 5,120,754, 5,223,522 (=Japanese Patent Application (Kokai) No. Hei 1-272573); U.S. Pat. Nos. 5,002,953, 5,194,443, 5,232,925, 5,260,445 (=Japanese Patent Application (Kokai) No. Hei 1-131169); U.S. Pat. No. 4,918,091 (Japanese Patent Application (Kokai) No. Sho 64-13076); U.S. Pat. Nos. 4,897,393, 4,948,900 (=Japanese Patent Application (Kokai) No. Sho 64-56675=Japanese Patent Publication (Kokoku) No. Hei 5-5832); U.S. Pat. No. 4,873,255 (=Japanese Patent Application (Kokai) No. Sho 64-38090); U.S. Pat. No. 4,703,052 (=Japanese Patent Application (Kokai) No. Sho 61-271287=Japanese Patent Publication (Kokoku) No. Hei 5-86953); U.S. Pat. No. 4,687,777 (=Japanese Patent Application (Kokai) No. Sho 61-267580=Japanese Patent Publication (Kokoku) No. Hei 5-31079); U.S. Pat. No. 4,725,610 (=Japanese Patent Application (Kokai) No. Sho 61-85372=Japanese Patent Publication (Kokoku) No. Hei 5-66956); U.S. Pat. No. 4,572,912 (=Japanese Patent Application (Kokai) No. Sho 60-51189=Japanese Patent Publication (Kokoku) No. Hei 2-31079); U.S. Pat. No. 4,461,902 (Japanese Patent Application (Kokai) No. Sho 58-118577=Japanese Patent Publication (Kokoku) No. Hei 2-57546); U.S. Pat. Nos. 4,287,200, 4,340,605, 4,438,141, 4,444,779 (=Japanese Patent Application (Kokai) No. Sho 55-22636=Japanese Patent Publication (Kokoku) No. Sho 62-42903); EP 0708098A (=Japanese Patent Application (Kokai) No. Hei 9-48779); EP 0676398A (=Japanese Patent Application (Kokai) No. Hei 7-330728); WO 95/18125; EP 0745600A; EP 0332332A (=Japanese Patent Application (Kokai) No. Hei 1-272574) and EP 0604983A (=Japanese Patent Application (Kokai) No. Hei 6-247945), etc. Furthermore, the equal sign "=" indicates the corresponding patent or patents.
For example, 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine -2,4-dione (referred to as "troglitazone") is a thiazolidine derivative having activity that enhances insulin effects, and is known as an agent for the prevention and/or treatment of diabetes [Fujiwara, et al., Diabetes, Vol. 37, p. 1459 (1988); Hofmann, C. A. et al., Diabetes Care, Vol. 15, p. 1075 (1992)]. Moreover, since said compound has antioxidation effects, it is also reported to be useful as a therapeutic drug for insulin-dependent diabetes mellitus (type I diabetes: IDDM) [Tounyoubyou, Vol. 37, No. 2, pp. 127-129 (1994)].
However, there are no reports that troglitazone inhibits tissue invasion of lymphocytes, and that it is useful as a preventive and/or therapeutic agent of autoimmune diseases with the exception of insulin-dependent diabetes mellitus (type I diabetes). At present, insulin-dependent diabetes mellitus (type I diabetes) is considered to be a type of autoimmune disease. Although there is only one report indicating that troglitazone is useful for the treatment of insulin-dependent diabetes mellitus, this states the finding that troglitazone is useful for treatment or prevention of insulin-dependent diabetes mellitus is based on the antioxidation effects possessed by said compound. Thus, these known facts do not instruct or suggest that troglitazone inhibits tissue invasion of lymphocytes or that it is useful as a preventive and/or therapeutic agent for autoimmune diseases (excluding type I diabetes). Moreover, although it is known that other substances that improve insulin resistance are useful for treatment and prevention of diabetes, it is not known that these compounds inhibit tissue invasion of lymphocytes.